ISSN
1916-694X

2010;
Volume 1 (Number 2): Pages 29-38

REVIEW ARTICLE

Pharmacokinetic profile of the antifungal
agent posaconazole

Dominique LEVEQUEa,b*, Yasmine
NIVOIXa, François JEHLb, Geneviève
UBEAUD-SEQUIERa, Raoul HERBRECHTc

aPharmacy-Pharmacology, Hôpital
Hautepierre, bInstitute of Bacteriology,  and cDepartment of Oncology
and Hematology, Hôpital Hautepierre; Strasbourg, France

*Corresponding
author: [email-masked]

ABSTRACT

Posaconazole is a recent triazole
antifungal agent currently available in an oral suspension. It is approved in
the treatment of various refractory invasive fungal diseases and for
prophylaxis in high-risk patients. This review presents the published clinical
pharmacokinetic data of posaconazole. Aspects regarding absorption,
distribution, elimination, and pharmacokinetic interactions are also discussed.

Key words

Drug-drug interactions; Pharmacokinetics;
Posaconazole

RÉSUMÉ

Le posaconazole
est un agent antifongique récent, appartenant à la classe des
triazolés et disponible sous forme de suspension buvable. Il est
indiqué dans le traitement d’infections fongiques invasives
réfractaires ainsi qu’en prophylaxie chez des patients à
haut risque. Cette mise au point présente les données
pharmacocinétiques publiées du posaconazole chez l’homme.
Les aspects concernant l’absorption, la distribution,
l’élimination, et les interactions médicamenteuses sont
notamment abordées.

Mots clés

Interactions
médicamenteuses; Pharmacocinétique; Posaconazole;

RESUMEN

Posaconazole
es un antimicótico triazol relativamente nuevo, disponible en forma de
suspensión oral. El fármaco está aprobado para el tratamiento
de de diversas micosis refractarias e invasivas así como para la
profilaxis en pacientes de alto riesgo. Esta revisión presenta los datos
farmacocinéticos del posaconazol. También se discuten aspectos
relacionados a la absorción, distribución, eliminación e
interacciones medicamentosas.

Palabras clave

Interacción
medicamentosa; Farmacocinética; Posaconazol

INTRODUCTION

Posaconazole (formerly SCH56592) is a recent
systemic antifungal agent (approved in Europe and in the United States in 2006)
that belongs to the azoles chemical family. Currently, the pharmacological
treatment of invasive fungal diseases comprises of the polyenes (amphotericin B
and its lipidic/liposomal formulations), the azoles, the echinocandins
(caspofungin, micafungin, anidulafungin), the alkylamines/thiocarbamates
(terbinafine), and the fluoropyrimidines (fluorocytosine).

Other than ketoconazole, all commonly used
systemic azoles are triazoles (three nitrogen in the 5-membered azole ring).
This group currently includes fluconazole, itraconazole, voriconazole and
posaconazole. In the European Union, posaconazole is licensed for the treatment
of adult patients with various refractory invasive infections (aspergillosis,
fusariosis, chromoblastomycosis, and coccidioidomycosis) and those with
oropharyngeal candidiasis. It is also approved as prophylactic treatment of
invasive fungal infections in high-risk patients such as those receiving
chemotherapy for acute myelogenous leukemia or those treated for a severe
graft-versus-host disease after allogeneic hematopoietic stem-cell
transplantation. This review summarizes the published pharmacokinetic data for
posaconazole in humans.

PHARMACOLOGICAL PROPERTIES

Posaconazole is an enzyme inhibitor that
blocks the synthesis of ergosterol, a constituent of fungal membranes, and
thereby hinders the growth of the microorganism. Posaconazole binds in the
active site of the P-450-dependent enzyme lanosterol 14α-demethylase
(CYP51 or Erg11p) and ligates the iron heme cofactor through a nitrogen atom [1] [2]. This inhibition leads to depletion of ergosterol and
accumulation of 14α-methyl sterols, such as lanosterol, affecting the
integrity and the function of the fungal membrane [3]. The IC50 (concentration leading to a 50%
decrease in ergosterol synthesis in fungi extracts) are lower than the MIC
(minimal inhibitory concentrations) for some Candida species, around 7 µg
L-1 for Candida albicans
(MIC: 60 µg L-1) and 300 µg L-1 for Candida glabrata (MIC: 4 mg L-1)
[3]. Regarding Aspergillus
strains, posaconazole displays IC50 comparable to MIC,
approximately 30 µg L-1 [3]. Posaconazole is a broad-spectrum antifungal showing in vitro and in vivo activity against Candida
spp., including most fluconazole-resistant C albicans and C krusei, Aspergillus spp., including some
itraconazole, voriconazole and amphotericin B-resistant Aspergillus fumigatus, Cryptococcus
neoformans, Fusarium species, zygomycetes and endemic fungi such as Blastomyces dermatitidis, Coccidioides immitis [4].

Drug formulation and administration

Posaconazole is administered orally and,
currently, is only formulated in a suspension in polysorbate 80 (surfactant) at
40 mg mL-1. A tablet form has been investigated but has not been
licensed due to dissolution problems. Hence, exposure to posaconazole after
intake of the suspension was enhanced by 1.3 fold when compared with the tablet
[5]. In addition, an intravenous formulation is in
development. Posaconazole is administered at 400 mg once every 12 hours or 200
mg once every 6 h in the management of refractory invasive infections. The oral
regimen for oropharyngeal candidiasis is 200 mg the first day and then 100 mg
once a day for 13 days. For prophylaxis, it is given at 200 mg three times
daily. To insure maximal absorption (see below), posaconazole must be taken
with a meal or a nutritional supplement.

Analytical methodology

Structurally, posaconazole (molecular weight
or MW: 700.8) is highly related to itraconazole (MW: 705.6) mostly differing by
the replacement of 2 fluorine atoms by two chlorine in the phenyl ring. As with
itraconazole, posaconazole is very lipophilic and is insoluble in water at
physiologic pH. To date, various validated assays regarding the analysis of
posaconazole in human plasma and urine have been published [6] [7] [8] [9] [10]. As an antiinfective agent, voriconazole has been
quantitated in plasma by a classical microbiological assay (bioassay) [6], by liquid chromatography with ultraviolet (UV)
detection set at 255 or 262 nm [7] [8] or tandem mass spectrometric detection [9] [10].

The techniques using UV detection or mass
spectrometry exhibit comparable lower limits of quantitation (LOQ) in plasma
(range 0.001 mg L-1 to 0.050 mg L-1) that are sufficient
for determination of terminal half-lives at therapeutic dosages. The LOQ in
urine was 0.035 mg L-1 [10]. The LOQ in plasma (bioassay) was 0.62 mg L-1
[6]. The bioassay, which measures an activity rather than
a quantity, is not suitable for patients receiving an association and is
inferior to chromatographic methods in terms of precision and accuracy.
However, it constitutes a means to detect the presence of eventual active
metabolites.

Absorption

Posaconazole is a high permeability/low
solubility drug and belongs to the class II of the Biopharmaceutics
Classification System (BCS) [11]. Thus, it is considered to have a high intestinal
absorption after oral dosing. However, efflux transporters might affect the
extent of intestinal absorption. Molecular determinants controlling intestinal
absorption have partially been identified. According to the manufacturer,
posaconazole interacts with the drug transporter P-glycoprotein (P-gp; also
referred as ABCB1), encoded by the gene MDR1, as a ‘substrate’ and
as an inhibitor (unpublished data). This suggests that P-gp expressed at the apical
side of enterocytes might limit the transcellular passage of the azole, due to
an efflux in the intestinal lumen. Unfortunately, the absolute bioavailability
of oral posaconazole is unknown due to the lack of coupled intravenous kinetic
data.

Table 1

Pharmacokinetic
parameters for single oral dose posaconazole in adults

Subjects

Dose

(mg)

Sampling

period

(h)

Cmax

(mg
L-1)

Tmax

(h)

AUC0-t

(mg
h-1 L-1)

Vd/F

(L)

Cl/F

(mL min-1)

t½

(h)

Healthy

volunteers*
Tablet

6

50

120

0.11

(46)

6.3

(51)

2.3

(50)

511

(32)

389

(40)

15.9

(18)

6

100

120

0.23

(26)

7.3

(36)

6.1

(28)

431

(20)

275

(21)

18.3

(13)

6

200

120

0.33

(21)

5.8

(35)

10.3

(30)

674

(18)

341

(40)

24.5

(22)

6

400

120

0.61

(31)

6.3

(44)

19.4

(33)

781

(49)

363

(35)

24.1

(24)

6

800

120

1.3

(26)

6.2

(46)

46.9

(40)

594

(19)

320

(48)

24.4

(33)

6

1200

120

0.93

(28)

8.8

(85)

41.7

(42)

1,341

(58)

585

(73)

28.5

(26)

Patients**
Suspension

7

200,
once a day

24

0.12
± 74

7.6

1.9
± 1.1

NR

NR

NR

15

400,
once a day

24

0.19

± 126.7

8.2

2.9
± 2

NR

NR

NR

7

200,
qid

24

0.12
± 58.5

4.3

2.9
± 1.1

NR

NR

NR

Cmax : Peak concentration; Tmax: time to Cmax;
AUC: area under the serum concentration-time curve; Vd/F: apparent volume of
distribution; Cl/F : apparent clearance, t½: terminal
half-life; NR: not reported; qid = four times a day.

Results are expressed as mean (CV %) or mean ± SD.

* Reference [12]; **Reference [13].

Table 2

Pharmacokinetic
parameters for multiple oral doses posaconazole in adults

Subjects

Dose

(mg)

Sampling

Period

(h)

Cmax

(mg L-1)

Tmax

(h)

AUC0-t

(mg h-1 L-1)

Vd/F

(L)

Cl/F

(mL min-1)

t½

(h)

Healthy

volunteers*

Tablet;
twice a day (day 14)

9

50

120

0.37

(30)

9

(34)

3.8

(36)

365

(29)

225

(34)

19.2

(16)

9

100

120

1.0

(42)

11

(16)

10.2

(40)

343

(24)

172

(32)

24.1

(20)

9

200

120

1.3

(27)

10

(19)

14.3

(27)

467

(32)

232

(34)

23.9

(26)

9

400

120

3.2

(19)

9

(32)

33.9

(21)

486

(34)

192

(25)

31

(46)

Patients**

Suspension;
once daily

(last
day of dosing)

7

200

24

0.26
± 0.20

3.9

4.5  ±  2.9

NR

990.8
± 516.7

NR

15

400

24

0.35
± 0.16

6.9

6.4
± 3.2

NR

1,506.7

±
1,201.7

NR

7

200

24

0.48
± 0.19

10.3

8.7  ±3.3

NR

1,485.5

±
873.5

NR

Cmax : Peak concentration; Tmax: time to Cmax;
AUC: area under the serum concentration-time curve; Vd/F: apparent volume of
distribution; Cl/F : apparent clearance, t½: terminal
half-life; NR: not reported.

Results are expressed as mean (CV %) or mean ± SD.
*Reference [12]; **Reference [13].

When given orally, once a day in healthy
male volunteers, at single dosages ranging from 50 mg to 1,200 mg, posaconazole
(in tablet form) is slowly absorbed with a mean time to peak plasma concentration
(Tmax) varying between 6 and 9 h [12].

The corresponding maximum plasma
concentrations (Cmax) increased linearly from 0.11 mg L-1
(50 mg) to 1.32 mg L-1 (800 mg) (Table 1).
Above 800 mg, the exposition showed saturation (i.e., no increase in the Cmax
and in the area under the plasma concentrations-time curve or AUC) most likely
attributed to its low solubility in the digestive tract fluids [12]. Oral pharmacokinetics have been studied in 29
patients who were administered once daily posaconazole 200 or 400 mg formulated
in oral suspension (single dose) [13]. When compared with healthy volunteers receiving
tablets, the Tmax were comparable (7-8 h) except in patients who
received the drug four times a day due to the short dosing interval (Table 1).

Distribution

The plasma protein binding of posaconazole
is high, around 98% [14]. No data regarding its diffusion in specific tissues
have been yet reported. For example, posaconazole has shown clinical activity
in the management of central nervous system fungal infections, but its
diffusion in the cerebrospinal fluid as a surrogate of CNS penetration remains
to be determined [15].

Metabolism

When assessed in 8 healthy volunteers,
unchanged posaconazole recovered in urine and feces accounted for 76.3% of the
radioactive oral dose thus indicating a low metabolism [10].

In plasma, a glucuronide of posaconazole was
the major metabolite accounting for 17.7% to 27.6% of the radioactivity [10]. In vitro,
incubation of posaconazole in human liver microsomes resulted in the formation
of a glucuronide [16]. The biotransformation was catalyzed by the uridine
diphosphate-glucuronosyltransferase (UGT) 1A4. According to the microbiological
assay, there is no biologically active metabolite of posaconazole in human
plasma [6].

Excretion

Posaconazole appeared excreted predominantly
by the biliary route as unchanged drug. When determined in 8 healthy
volunteers, the feces (that also includes the unknown non-absorbed fraction)
contained 76% of an oral radioactive dose of posaconazole [10]. Most of the fecal radioactivity (66.3%) was
associated to the parent drug, the remainder corresponding to various minor
metabolites. The renal route accounted for 14% of the oral radioactive dose of
posaconazole, predominantly (10%) as unchanged drug [10].

Pharmacokinetic parameters

The pharmacokinetics of posaconazole in
adults is presented in Table 1 and Table
2. Since the absolute bioavailability is unknown, the systemic clearance
cannot be determined. Posaconazole exhibited linear pharmacokinetics up to 800
mg [12].

Given as a single oral dose (tablet), the
mean apparent clearance ranged between 275 and 389 mL min-1 and the
mean half-life ranged from 15.9 to 28.5 h. The apparent volume of distribution
varied between 431 and 781 L. At steady state (achieved by day 10), and given
twice a day (tablet), the apparent clearance was lower due to accumulation,
ranging between 172 and 232 mL min-1.

When compared with the single dose, the
terminal half-lives (19.2 to 24.1 h) and the apparent volumes of distribution
(365 to 486 L) were comparable at steady state [12]. Between Day 1 and Days 8-14, exposures (AUC0-24h)
increased 2-3 folds in patients who received the oral suspension [13]. This is not surprising since the dosing interval (12
h) was shorter than the terminal half-life.

SPECIAL POPULATIONS

Children

Posaconazole is currently not approved in
children in the European Union. In the United States, it is approved in
children 13 years of age and older for prophylaxis of Candida and Aspergillus
infections. Partial pharmacokinetic data have been obtained in 12 young
patients aged 8-17 years who received posaconazole oral suspension (800 mg
daily in divided doses) [17]. At steady state, the plasma concentrations were
judged comparable to those obtained in adults (around 0.8 mg L-1).
Elimination PK parameters were not reported.

Renal dysfunction

The renal route is a minor pathway for the
elimination of posaconazole. Thus, its disposition is not expected to be
altered by renal dysfunction. This was confirmed in a study that assessed
posaconazole kinetics in 18 subjects with various degrees of renal insufficiency
(creatinine clearance or Clcr ranging from < 20 mL min-1
to 80 mL min-1) and who received a single dose (400 mg) of oral suspension
[14]. Expositions (AUC extrapolated to infinity) were
comparable to those calculated in healthy subjects with normal renal function
(i.e. Clcr > 80 mL min-1). In addition, it was shown
that hemodialysis did not affect posaconazole plasma concentrations in 6
patients with severe renal insufficiency [14].

Hepatic dysfunction

Considering the biliary excretion of
posaconazole, an increase in the exposure might be encountered in patients with
hepatic impairment. Preliminary data published in an abstract form indicated
that exposure to posaconazole (single 200 mg dose of oral suspension) was
enhanced by 1.3 fold in 4 patients with severe hepatic dysfunction when
compared to that obtained in 4 normal subjects [18]. However, no recommendations regarding an adjustment
of dose in patients with hepatic dysfunction have been issued.

FACTORS
ALTERING THE PHARMACOKINETICS OF POSACONAZOLE

Food

Given the physico-chemical characteristics
of posaconazole (low solubility, high permeability), food, particularly
high-fat meal, is expected to increase its intestinal absorption, in relation
with an improved solubilization. The effect of food on posaconazole disposition
has been studied in 20 healthy volunteers [5]. After a single dose (200 mg) of oral suspension the
AUC0-72h of posaconazole, given with a high-fat breakfast, was
increased 3.9 fold when compared with that obtained in the fasting state. When given
with a nonfat meal, the AUC0-72h of posaconazole increased 2.7 fold [5]. Due to the fact that high-risk patients (those
candidate to antifungal prophylaxis) might have difficulties eating solid food,
the effect of a nutritional supplement on posaconazole kinetics has been tested
in 24 healthy volunteers [19]. Again, the AUC0-72h of posaconazole (400
mg, single dose of oral suspension) given with the oral supplement was shown to
be increased 2.5 fold when compared to that calculated in the fasted state.
Hence, the package insert recommends the intake of posaconazole oral suspension
with a meal or a nutritional supplement to ensure optimal exposure.

Dosing schedule

Reducing the dosing interval has been shown
to increase exposure. In 18 fasted healthy volunteers, administration of 400 mg
(suspension) every 12 hours or 200 mg every 6 h led to 2 fold and 3 fold
increases in the posaconazole exposure (AUC0‑48h), respectively,
when compared to the single daily dose (800 mg) [20]. In an another study including 61 patients, the
exposure to posaconazole (oral suspension) was shown to increase 1.8 fold, at
steady state, when the daily dose (800 mg) was split in two [21]. Despite its long terminal half-life but in relation
with its poor solubility, posaconazole oral suspension has to be given in
divided doses.

Age

The pharmacokinetics of posaconazole (400 mg
twice a day) has been studied in 24 elderly subjects (65-85 years) [22]. At steady state, the AUC0-12h was 1.3
fold higher than those obtained in 24 young subjects (18-45 years). Given the
high interpatient variability (40% in both groups), the difference was not
judged relevant. According to the official labeling, no dose adjustment is
needed in elderly patients.

Body weight, body surface area

In young patients (age: 8-17 years; body
weight: 24-76 kg), body weight or body surface area did not account for the
interindividual variability of plasma concentrations at steady state [17]. In adult patients, body weight did not influence
posaconazole exposure at steady state, thus justifying the use of a fixed dose
as for other azoles, except voriconazole [21] [22] [23].

Pharmacogenetics

As seen above, posaconazole is transported
by P-gp. Some genetic variants for MDR1 (in particular the single-nucleotide
polymorphism or SNP C3435T) have been associated with variation of P-gp
expression and, therefore, in alterations of pharmacokinetics [24]. No association between C3435T MDR1 genetic variant
and exposure to oral posaconazole has been found in 56 subjects [22]. It could mean that variability in intestinal P-gp
expression in relation with the variant C3435T has no significant impact on
oral absorption of posaconazole.

Other factors

Neither gender nor ethnicity has been shown
to influence posaconazole pharmacokinetics [22].

Pharmacodynamics

High interindividual kinetic variability
(i.e., coefficient of variation or CV in the 40-80% range regarding AUC) has
been reported in patients receiving posaconazole [13] [21]. Higher plasma concentrations of posaconazole have
been associated with greater responses rates in 67 patients with invasive
aspergillosis and who received the triazole at 800 mg in divided doses [25]. For example, optimal response rate (75%; 12/16
patients) was obtained at an average plasma concentration of 1.25 mg L-1.
In high risk patients receiving posaconazole at 200 mg thrice daily as
prophylactic treatment, lower plasma concentrations were observed in 4 of 5 patients
who developed invasive fungal infection when compared to those of 241 patients
without infection (median average concentrations: 0.61 mg L-1 vs.
0.92 mg L-1) [23]. As with oral itraconazole, monitoring of plasma
concentrations of posaconazole might be warranted to avoid underexposures,
although no target values for treatment of invasive fungal infections and
prophylaxis are available so far.

DRUG-DRUG INTERACTIONS

Pharmacokinetic interactions commonly occur
via drug-metabolizing enzymes or drug transporters. As mentioned earlier, posaconazole
is eliminated as unchanged drug, predominantly via biliary excretion. P-gp
expressed at luminal side of hepatocytes might mediate transport into the bile.
Biotransformation represents a minor route of elimination and is catalyzed by
UGT1A4. Theoretically, only non-metabolic interactions are anticipated, for
example with inhibitors or inducers (i.e., drugs activating orphan nuclear receptors)
of drug transporter expression.

The potential for posaconazole to modify the
kinetics of co-administered appears high. As for some of its congeners
(itraconazole, ketoconazole), posaconazole is a dual CYP3A4 and P-gp inhibitor.
In vitro, the IC50
regarding CYP3A4 activity for dextromethorphan N-demethylation is 1.3 µM
(0.91 mg L-1), in the range of the Cmax obtained at steady
state, after ingestion of the oral suspension (400mg twice daily) but much
higher than the unbound plasma concentration [26]. In vivo,
posaconazole (200 mg once daily) increased the AUC of intravenous midazolam
(probe drug for CYP3A inhibition) by 1.8 fold [26], meaning that the hepatic unbound concentration of
the azole is higher than that determined in plasma and is sufficient to inhibit
CYP3A activity (i.e., CYP3A4 and CYP3A5).

Based on current recommendations it is
difficult to classify posaconazole as a strong, moderate, or weak CYP3A
inhibitor because it has not been tested at its highest dose (i.e., 800 mg)
with the oral form of midazolam (more sensitive substrate than the intravenous
form) [27]. In addition, the inhibitory potency towards CYP3A5
is not known. Hepatic CYP3A expression is variable in relation, among others,
with genetic mutations of CYP3A5. Besides the substrate, the extent of CYP3A
inhibition by an azole may vary with the expression of CYP3A5 (in general, low
in Caucasians when compared with African Americans) and the respective
inhibition potency towards CYP3A4 and CYP3A5 (fluconazole is a more potent
inhibitor of CYP3A4 than CYP3A5) [28]. However, and without any kinetic documentation,
posaconazole is contraindicated with CYP3A4 substrates whose increased exposure
can cause dramatic effects like ergot alkaloids, drugs known to prolong QT
interval (quinidine), or some 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (i.e., simvastatin, atorvastatin). In vitro, posaconazole did not inhibit CYP1A1, CYP2C8/9, CYP2D6,
and CYP2E1 [26]. Unlike its congeners, it is not known whether
posaconazole interacts as an inhibitor with the transporter breast cancer
resistance protein (BCRP or ABCG2) expressed in the intestine and in the liver
canalicular membrane. Regarding P-gp, the inhibitory potential of posaconazole
has not been described (data from the manufacturer) and does not appear in the
product information.

Given the profile of inpatients receiving
posaconazole (intensive care units, oncology-hematology units), the interacting
drugs of concern are mainly immunosuppressants, anticancer drugs, some
analgesics and hypnotics. Most of the studies exploring drug-drug interactions
have been performed in healthy volunteers and have been conducted by the
manufacturer.

Drugs that potentially increase posaconazole
concentrations

Drugs that inhibit P-gp transport
(erythromycin, verapamil) might affect posaconazole disposition by enhancing
its absorption and/or decreasing its biliary secretion. Currently, no
pharmacokinetic data of posaconazole given with a P-gp inhibitor have been
reported.

Drugs that potentially decrease posaconazole
concentrations

Antiacids

Drugs whose oral absorption is dependent on
acid gastric pH like some azoles (ketoconazole, itraconazole) might be affected
by antiacids. Coadministration of an aluminium/magnesium containing antiacid
did not significantly alter posaconazole absorption in fasting or non-fasting
healthy volunteers [29]. In contrast, coadministration of cimetidine (400 mg
twice daily), an histamine H2-receptor antagonist, with posaconazole
tablets (200 mg once daily with food) lead to a 40% decrease in azole exposure
and Cmax [30]. The terminal half-life was not affected underlining
the likely decrease in absorption. Thus, it is recommended to avoid the association
of posaconazole with a histamine H2-receptor antagonist or proton
pump inhibitor.

Rifampin,
rifabutin

Rifampin or rifabutin are pleiotropic
inducers increasing the expression of enzymes or transporters. They interact
with orphan nuclear receptors like pregnane X receptor (PXR or SXR) or constitutive
androstane receptor (CAR) that act as transcriptional factors regulating the
expression of genes coding for pharmacokinetic determinants [31]. When combined with rifabutin (300 mg once a day for
17 days), the exposure of posaconazole given 200 mg once daily in 24 healthy
males decreased by 49%, at steady state [32]. The interaction might be imputable to increased
expression of UGT1A4 and P-gp. The interaction with rifampin, considered to be
the strongest inducer due to its slower elimination (relative to rifabutin),
has not been investigated. According to the package insert, association of
posaconazole with rifampin or rifabutin must be avoided.

Phenytoin

Phenytoin is an inducer of human CYP3A4 and
CYP2B6 presumably via activation of the nuclear receptors PXR and CAR, respectively
[31]. Phenytoin has not been shown to induce expression of
known posaconazole kinetic determinants. Surprisingly, data published in an
abstract form reported that the apparent clearance of posaconazole (200 mg once
a day) increased by 90% in 36 healthy volunteers when combined with phenytoin
(200 mg once a day) [33]. The mechanism relative to the increase in posaconazole
elimination is currently unknown. According to the package insert, this
association should be avoided.

Drugs kinetics altered by posaconazole

Midazolam

As seen above, posaconazole (200 mg) increased
intravenous midazolam exposure 1.8 fold in 12 healthy volunteers, in relation
with the CYP3A catalyzed metabolism inhibition of the hypnotic [26][26].
Therefore, dose reduction of midazolam (and benzodiazepines such as alprazolam,
triazolam) should be performed while co-administrated with posaconazole.

Tacrolimus

Coadministration of posaconazole (400 mg
twice daily for 8 days) and tacrolimus (0.05 mg kg-1 day-1)
in 36 healthy volunteers lead a 4.2 fold increase in the AUC of the
immunosuppressive agent suggesting an inhibition of hepatic biotransformation
catalyzed by CYP3A4 and a potential limitation of an intestinal first pass
effect involving CYP3A4 and P-gp [34]. It is recommended to decrease tacrolimus dose by 33%
when the treatment with posaconazole is initiated. Coadministration of an azole
strengthens the monitoring of tacrolimus blood concentrations.

Cyclosporine

Administration of oral posaconazole (200 mg
daily) to 4 heart transplant subjects under stabilized oral cyclosporine
therapy increased the dose-normalized exposure to the immunosuppressant by 33%,
leading to 14-29% reduction of cyclosporine dosage in 3 patients [34]. Cyclosporine-increased exposure is probably related
to the inhibition of P-gp and CYP3A4 by posaconazole. Overall, cyclosporine
dosage must reduced by 25% at the beginning of treatment with posaconazole.
Blood concentrations must be carefully monitored thereafter (as usual).

Vincristine

A severe peripheral neurotoxicity has been
reported in a young patient with acute lymphoblastic leukemia who received
intravenous vincristine with oral posaconazole [35]. Vincristine is transported by P-gp and its
metabolism was recently (2006) shown to be catalyzed by CYP3A4 and CYP3A5 [36]. Although the pharmacokinetics of vincristine was not
investigated, posaconazole might have delayed the elimination of the anticancer
drug. Thus, the association of posaconazole with Catharanthus
(‘vinca’) alkaloids (vinblastine, vincristine, vinorelbine) is not
recommended.

CONCLUSIONS

Posaconazole pharmacokinetic profile is
characterized by a saturated oral absorption when daily dosage exceeds 800 mg,
in relation with its lipophilicity and an unknown absolute bioavailability due
to the lack of intravenous kinetic data. In corollary, the systemic clearance
is undetermined. Drug exposure increases with repeated administration and is
optimized when the antifungal agent is given with food or an oral supplement,
in divided doses, regardless of its long terminal half-life. Association of
posaconazole with orphan nuclear receptors interacting drugs
(“inducers”) must be avoided because it can lead to therapeutic
failures. In addition, posaconazole has the potential to alter the
pharmacokinetics of co-administered drugs in relation with the inhibition of
P-gp drug transport and/or CYP3A4 activity. Several significant interactions
have been reported and numerous others are suspected (digoxin, sirolimus).

AUTHORS’ PARTICIPATION

D L designed the paper, collaborated in the
first draft and reviewed final version of the manuscript. YN helped to analyze
the information and collaborated in the first draft. F J and G U-S reviewed the
final paper. R H helped to analyze the information and reviewed the final
version of the manuscript.

ACKNOWLEDGEMENTS

None.

CONFLICT OF INTERESTS/DISCLAIMERS

Y N, F J, G US: none to declare. D L is
member of the Editorial Board of the journal. R H has served as a consultant
for Gilead, Pfizer, Schering-Plough, Merck Sharp & Dohme, Astellas, and
Novartis and has received grant support from Pfizer.

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